Accelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (Beckman et al., 2002, JAMA 287:2570-2581; D'Souza et al., 2009, Mol. Cell. Biochem. 331:89-116; Kannel & McGee, 1979, JAMA 241:2035-2038). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis and increased coagulation factors, as well as abnormal platelet function, are typical for diabetes, contributing to the increased thrombotic events and development of arteriosclerosis (Carr, 2001, J. Diabetes Complications 15:44-54). Altered platelet function in diabetes mellitus (DM), including altered adhesion and aggregation, may participate in the pathogenesis of diabetic vascular complications by promoting microthrombus formation (Bern, 1978, Diabetes 27:342-350; Brownlee, 2001, Nature 414:813-820; Gugliucci, 2000, J. Am. Osteopath. Assoc. 100:621-634; Wautier & Guillausseau, 1998, Vase. Med. 3:131-137), contributing to enhanced risk of small vessel occlusions and accelerated atherothrombotic diseases (Carr, 2001, J. Diabetes Complications 15:44-54; Calles-Escandon et al., 1999, Coron. Artery Dis. 10:23-30; De Cristofaro et al., 2003, J. Thromb. Haemost. 1:250-256). Patients with Type 2 (T2) DM exhibit platelet hyper-reactivity both in vitro and in vivo, coupled with biochemical evidence of persistently increased thromboxane (TX)-dependent platelet activation (Davi et al., 1990, N. Engl. J. Med. 322:1769-1774; Ferroni et al., 2004, J. Thromb. Haemost. 2:1282-1291; Watala et al., 2005, Pharmacol. Rep. 57 Suppl:42-5). The mechanism by which platelets transduce glucose levels into enhanced TX generation independent of endothelial and other blood cell derived factors remains unclear. Similarly, optimal antiplatelet therapy for diabetic patients remains to be achieved.
Aldose reductase (AR) is the first enzyme of the polyol pathway, and it represents a minor source of glucose utilization, accounting for less than 3% of glucose consumption under euglycemia. However, under hyperglycemia, the activity of AR is substantially increased, representing up to 30% of total glucose consumption, and the abnormal activation of the polyol pathway leads to depletion of reducing equivalents and accumulation of osmotically active polyols (Bhatnagar & Srivastava, 1992, Biochem. Med. Metab. Biol. 48:91-121). Therefore, enhanced utilization of this pathway is well known to contribute to microvascular and macrovascular diabetic complications by increasing the oxidative and osmotic stress. Also, the pharmacological inhibition of AR has been shown to reduce the frequency of polyneuropathy and retinopathy in DM patients (Bhatnagar & Srivastava, 1992, Biochem. Med. Metab. Biol. 48:91-121; Baynes & Thorpe, 1999, Diab. 48:1-9; Ramana et al., 2002, J. Biol. Chem. 277:32063-32070). In fact, it has been shown that human AR expression in transgenic mice accelerates the diabetic atherosclerosis (Vikramadithyan et al., 2005, J. Clin. Invest. 115:2434-2443), implying that AR may play an important role in atherothrombosis.
There is a need in the art to develop a novel method of preventing or treating abnormal thrombus formation and subsequent cardiovascular disease in diabetic patients and patients with increased cardiovascular risk, such as patients with coronary syndrome, cerebrovascular disease (such as stroke), peripheral vascular disease and coronary artery disease. The present invention fulfills this need.